, Volume 236, Issue 9, pp 2557–2568 | Cite as

Unidirectional opioid-cannabinoid cross-tolerance in the modulation of social play behavior in rats

  • Sara Schiavi
  • Antonia Manduca
  • Marco Segatto
  • Patrizia Campolongo
  • Valentina Pallottini
  • Louk J. M. J. Vanderschuren
  • Viviana TrezzaEmail author
Original Investigation



The endocannabinoid and the endogenous opioid systems interact in the modulation of social play behavior, a highly rewarding social activity abundantly expressed in young mammals. Prolonged exposure to opioid or cannabinoid receptor agonists induces cross-tolerance or cross-sensitization to their acute behavioral effects.

Objectives and methods

Behavioral and biochemical experiments were performed to investigate whether cross-tolerance or cross-sensitization occurs to the play-enhancing effects of cannabinoid and opioid drugs on social play behavior, and the possible brain substrate involved.


The play-enhancing effects induced by systemic administration of JZL184, which inhibits the hydrolysis of the endocannabinoid 2-AG, were suppressed in animals repeatedly pretreated with the opioid receptor agonist morphine. Conversely, acute morphine administration increased social play in rats pretreated with vehicle or with either JZL184 or the cannabinoid agonist WIN55,212-2. Acute administration of JZL184 increased the activation of both CB1 receptors and their effector Akt in the nucleus accumbens and prefrontal cortex, brain regions important for the expression of social play. These effects were absent in animals pretreated with morphine. Furthermore, only animals repeatedly treated with morphine and acutely administered with JZL184 showed reduced activation of CB1 receptors and Akt in the amygdala.


The present study demonstrates a dynamic opioid–cannabinoid interaction in the modulation of social play behavior, occurring in limbic brain areas strongly implicated in social play behavior. A better understanding of opioid–cannabinoid interactions in social play contributes to clarify neurobiological aspects of social behavior at young age, which may provide new therapeutic targets for social dysfunctions.


Cannabinoid Opioid Social play behavior Rats 2-AG Morphine 



This work was supported by 7th Framework Program People (Marie Curie Career Reintegration Grant PCIG09-GA-2011-293589 to V.T.) and Jerome Lejeune Foundation (grant no. 1674 to V.T.). This work was partially supported by Excellence Departments, MIUR‐Italy, Grant/Award Numbers: ARTICOLO 1, COMMI 314‐ 337 LEGGE 232/2016, ARTICOLO 1.

Compliance with ethical standards

Conflict of interest

The authors declare that, except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 5 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Supplementary material

213_2019_5226_MOESM1_ESM.pptx (86 kb)
Supplementary Figure 1 Total expression of CB1 cannabinoid receptor protein in the amygdala, nucleus accumbens (NAc) and prefrontal cortex (PFC) of rats repeatedly treated with morphine and acutely treated with JZL184. Animals injected for 5 days with morphine (MOR) and treated acutely with JZL184 (JZL) before testing showed no changes in the total expression of CB1 receptor protein in the amygdala (a), NAc (b) and PFC (c) when compared to all the other experimental groups. Data represent mean values ± SEM. (PPTX 85 kb)
213_2019_5226_MOESM2_ESM.pptx (12 mb)
Supplementary Figure 2 Uncropped images of Western blot experiments in the amygdala of rats repeatedly treated with morphine and acutely treated with JZL184. (PPTX 12284 kb)
213_2019_5226_MOESM3_ESM.pptx (10.2 mb)
Supplementary Figure 3 Uncropped images of Western blot experiments in the NAc of rats repeatedly treated with morphine and acutely treated with JZL184. (PPTX 10460 kb)
213_2019_5226_MOESM4_ESM.pptx (4.1 mb)
Supplementary Figure 4 Uncropped images of Western blot experiments in the PFC of rats repeatedly treated with morphine and acutely treated with JZL184. (PPTX 4175 kb)


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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Science, Section of Biomedical Sciences and TechnologiesUniversity “Roma Tre”RomeItaly
  2. 2.Department of Physiology and Pharmacology “V. Erspamer”Sapienza University of RomeRomeItaly
  3. 3.Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands

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